High prognostic value of p16INK4 alterations in gastrointestinal stromal tumors.

PURPOSE: Gastrointestinal stromal tumors (GISTs) represent a distinctive (but histologically heterogeneous) group of neoplasms, the malignant potential of which is often uncertain. To determine the prognostic relevance of p16INK4 alterations in GISTs, we investigated a larger group of GISTs and correlated the genetic findings with clinicopathological factors and patient survival. MATERIAL AND METHODS: We evaluated the methylation status of the promotor by methylation-specific polymerase chain reaction (PCR), the presence of mutations by PCR-SSCP-sequencing, the loss of heterozygosity at the p16INK4 locus (using the c5.1 marker), and the immunohistochemical expression of p16INK4 protein in 43 GISTs in 39 patients. RESULTS: p16INK4 alterations were found in 25 of 43 GISTs (58.1%), with benign, borderline, or malignant GISTs showing no differences in the type and frequency of alteration. p16INK4 alterations were correlated with a loss of p16INK4 protein expression (P <.01). Patients who had tumors with p16INK4 alterations had a poorer prognosis than patients with tumors without such alterations (P =.02). There was a high predictive value for p16INK4 alterations only in the group of benign and borderline GISTs (P <.01) with regard to clinical outcome. Univariate Cox's proportional hazard regression analysis revealed a strong correlation between p16INK4 alterations, tumor size, mitotic index, and overall survival (P <.02), whereas multivariate Cox's analysis confirmed only p16INK4 alterations as an independent prognostic factor. CONCLUSION: We believe that the evaluation of p16INK4 alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.     

Mononucleosis syndrome and coincidental human herpesvirus-7 and Epstein-Barr virus infection

Two girls (a 5 year old and a 21 month old) experiencing mononucleosis syndrome with coincidental human herpesvirus (HHV)-7 and Epstein-Barr virus (EBV) infections are described. One patient had primary HHV-7 infection and reactivated EBV infection. The other had primary HHV-7 and EBV infections. These cases indicated that HHV-7 is capable of inducing infectious mononucleosis-like illness. Multiple herpesvirus infection in one of the patients also suggests that interaction among herpesviruses can occur in vivo. The consequence of this interaction may have clinical implications.     

Preschool behavior disorders: their prevalence in relation to determinants

The occurrence of behavior disorders was investigated in a prospectively followed 3-year-old birth cohort. Of 1116 eligible children, the parents of 918 were successfully contacted. All agreed to complete a telephone interview and were mailed a Childhood Behavior Checklist (CBCL) standardized for 2- to 3-year-old children; 756 (82%) returned the CBCL. The prevalence of one or more of the deviant behavior syndromes identified by the CBCL was 11.1%. From a number of subject characteristics recorded throughout infancy, age-specific determinants for the occurrence of these deviant behaviors were identified. Characteristics most consistently associated with preschool psychopathology included the mother's ill health and lack of social support, the presence of chronic illness in the child, and the frequent use of hospital emergency services. These and other determinant (risk) indicators were entered into logistic regression (LR) models to derived adjusted relative risk estimates for the occurrence of a behavior disorder. The derived LR equations emphasize the important role of both the mother as well and the father and the health of the child.     

Detection of herpes simplex virus in women with acute pelvic inflammatory disease

Four women are described with acute salpingitis confirmed by laparoscopy who had herpes simplex virus (HSV) isolated from the cervix or the upper genital tract (endometrium, fallopian tube, or cul-de-sac) or both. None of the patients had overt genital herpes, but one had typical HSV cervitis on a cervicovaginal smear stained with Papanicolaou's stain, one had a significant change in level of antibodies to HSV, and one had an endometrial biopsy specimen positive for HSV antigen. There are at least three potential explanations for these findings: chronic viral shedding, viral reactivation caused by acute pelvic inflammatory disease (PID), or that the PID was actually caused by HSV. Further prospective studies are needed to document the role of HSV in causing PID.     

Bone Mineral Density in the Proximal Femur and Contralateral Knee After Total Knee Arthroplasty

Osteoarthrosis (OA) is often associated with pain and disability, which are relieved after total knee arthroplasty (TKA), but the nature of bone changes associated with OA is controversial. We examined preoperative hip and contralateral knee bone mineral density (BMD) in patients requiring TKA and monitored the BMD changes postoperatively. Sixty-nine patients, scheduled to have TKA for osteoarthrotic knees, had both hips and contralateral knee BMD measured by dual-energy X-ray absorptiometry (DXA) at the time of operation (baseline) and at 1 yr after operation. X-rays of the knee joints were also taken to evaluate the severity of OA. Preoperatively, 27% and 38% of the patients had total hip BMD Z-score more than 1 SD in the operated side and contralateral hips, respectively. In all regions of interest (ROI), the mean baseline BMD of the affected side proximal femur was significantly lower than that of the contralateral side (p < 0.0005-0.019). The severity of OA was not associated with BMD. During 1-yr follow-up, the postoperative knee status and the physical activity of the patients (AKS score) improved. However, neither the hip nor the nonoperated knee BMDs increased. Knee OA is associated with significantly lower BMD values in the affected side compared with the contralateral hip, and these levels remained similar or decreased during a 1-yr follow-up. We conclude that improved mobility after TKA does not improve the effects of preoperative disuse-associated bone loss in the short term.     

Periprosthetic tibial bone mineral density changes after total knee arthroplasty: one-year follow-up study of 69 patients

BACKGROUND: The critical structure supporting the prosthetic components in total knee arthroplasty (TKA) is tibial trabecular bone. The quality of tibial bone can be evaluated by bone mineral density (BMD) measurements. PATIENTS AND METHODS: We prospectively measured changes in BMD in the proximal tibia after cemented TKA in osteoarthrotic knees. 69 patients were scanned by dual-energy X-ray absorptiometry (DXA) within a week after surgery, and after 3, 6 and 12 months. RESULTS: At baseline, the medial region of interest (ROI) BMD was higher in the varus knees than in the valgus aligned knees (p=0.02). The medial metaphyseal ROI showed a decrease in BMD during the follow-up in preoperatively varus knee joints (p<0.001). In preoperatively valgus knees, there was a slight increase in medial compartment BMD which was not significant (p=0.2). Alignment correction in both groups showed bone remodeling giving similar medial and lateral BMD values, suggesting that the bone became equally strong in both compartments of the metaphysis. There was no association between increasing American Knee Society (AKS) scores and bone remodeling. INTERPRETATION: We suggest that this remodeling is caused by postoperative changes in tibial loading. Our results support the clinical importance of recreating proper valgus alignment of the knee joint in the TKA operation, thus possibly providing better conditions for longevity of the tibial component.     

Sterol parameters as markers of liver function in primary biliary cirrhosis before and after liver transplantation

Serum cholesterol reflects poorly cholesterol metabolism. From serum noncholesterol sterols cholestanol, campesterol, and sitosterol are surrogate markers of cholesterol absorption, but reflect also cholestasis, while those of lathosterol reflect cholesterol synthesis and hepatic parenchymal function. We investigated these sterols at end-stage of primary biliary cirrhosis (PBC) - prior to liver transplantation and shortly after transplantation in 67 patients to show their role as index of cholestasis and parenchymal liver function. Median preoperative values of cholestanol were increased 7.6 times, those of plant sterols 1.6-3.7 times above and the campesterol/sitosterol ratio was decreased twice below our control values, respective lathosterol levels being mainly subnormal. After transplantation, the proportions to cholesterol of the absorption markers decreased, and those of synthesis markers and the ratios of campesterol/sitosterol increased significantly. Thus, surrogate sterol markers of cholesterol absorption and synthesis in serum are also good clinical markers of chronic cholestasis and degree of hepatic parenchymal cell function in PBC. Postoperative improvement of serum sterol profile indicate clinically good function of the liver graft.     

Benign epithelioid peripheral nerve sheath tumors of the soft tissues: clinicopathologic spectrum of 33 cases

Benign epithelioid peripheral nerve sheath tumors (BEPNSTs) have not been fully characterized, and their relationship to conventional schwannoma and neurofibroma has not been satisfactorily established. Herein, we detail the clinicopathologic features of 33 examples of BEPNST. The study included 22 females and 11 males ranging in age from 2 to 68 years (median, 31.5 years). Only one patient probably has neurofibromatosis type 1. The tumors were predominantly dermal/subcutaneous in location (85%) and involved the lower limb (n=15), upper limb (n=11), trunk (n=4), and head/neck (n=3). The lesions ranged in size from 0.3 to 6.8 cm (median, 1.1 cm). Microscopically, the tumors were generally well-circumscribed, uninodular, or multinodular masses. Twenty-six lesions were encapsulated. Tumors consisted of trabeculae, loosely arranged nodules, and cohesive nests of epithelioid tumor cells immersed in collagenous, myxohyaline, or chiefly myxoid stroma. A bland spindled cell component comprising 5% to 40% of the tumor was noted in 15 cases. Mitotic activity ranged from 0 to 6 mitoses/50 high power fields (mean, 1.5 mitoses/50 high power fields) with no abnormal division figures identified. Five lesions were considered atypical based on presence of focal nuclear/nucleolar enlargement and hyperchromasia. Immunohistochemical reactivity for Schwann cell-related markers in tumor cells included S-100 protein (20 of 20 cases), collagen type IV (10 of 10), laminin (8 of 8), nerve growth factor receptor, p75(7 of 8), CD57 (6 of 9), and glial fibrillary acidic protein (8 of 15). CD34-positive fibroblast-like cells were identified in all 12 neoplasms tested. Anti-epithelial membrane antigen highlighted perineurial cells in 9 of the 11 encapsulated tumors. Anti-neurofilament protein did not identify intralesional neuraxons in the 10 tumors evaluated. Eighteen tumors were subtyped as epithelioid neurofibromas. The remaining 15 cases showed some histologic features suggestive of schwannoma, but their uniform cellularity, absence of nuclear palisading, and presence of a significant CD34-positive spindled cell population in 5 cases led to their classification as "BEPNST of indeterminate histogenesis." Evaluation for loss of heterozygosity in 2 cases demonstrated deletion of genetic material on chromosome 22q and 17q involving NF2 and NF1 loci. However, sequencing of NF2 coding sequences revealed no mutations. Follow-up for 18 patients (median interval, 13.5 years), including 4 patients with tumors exhibiting cytologic atypia, revealed a nondestructive recurrence or persistent disease in 3 patients whose tumors lacked atypia, but no evidence of metastatic spread or tumor-related death. BEPNSTs are usually small neoplasms located in superficial soft tissue and have an excellent prognosis after complete local excision. Accurate subclassification of some of these lesions is difficult based on currently available techniques.     

Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients

Low serum albumin and low serum cholesterol levels are among the most consistent predictors of mortality in patients with end-stage renal disease (ESRD) undergoing hemodialysis. Hypoalbuminemia is often interpreted as a marker of poor nutrition, but serum albumin and cholesterol levels can also be low as part of a cytokine-mediated acute-phase reaction to acute or chronic inflammation. Here we report the results from a 900-day prospective study designed to determine whether tumor necrosis factor-alfa (TNF-alpha) and interleukin-6 (IL-6) predict serum albumin and cholesterol levels and mortality in a group of 90 ambulatory, adult hemodialysis patients with no acute infection, hospitalization or surgery, and no known acquired immunodeficiency syndrome (AIDS), malignancy, or liver disease. Measurable levels of TNF-alpha and/or IL-6 were found in 89 of 90 patients. Significant relationships were found between TNF-alpha and IL-6 and the degree of hypoalbuminemia and dyslipoproteinemia. IL-6 was the strongest predictor of mortality in univariate and multivariate analysis, followed by age, albumin level, and body mass index (BMI). Although the cause of hypercytokinemia was not addressed in this study, the data support the view that hypoalbuminemia and hypocholesterolemia are negative acute-phase responses to inflammatory stimuli. These results suggest that efforts to identify the nature of the stimuli for cytokine production and to lower cytokine levels in hemodialysis patients might be effective in improving the survival of patients undergoing hemodialysis.